Mitogen-activated protein kinase (MAPK) cascades are key signaling pathways involved in the regulation of normal cell proliferation, survival and differentiation. Aberrant regulation of MAPK cascades contributes to cancer and other human diseases. In particular, the extracellular signal-regulated kinase (ERK) MAPK pathway has been the subject of intense research scrutiny leading to the development of pharmacologic inhibitors for the treatment of cancer.
In the MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) the signal starts when a signaling molecule binds to receptor tyrosine kinases (RTKs), leading to the activation of Ras proteins. Subsequently, a three-stage phosphorylation cascade takes place: activated Ras activates the protein kinase activity of Raf serine/threonine kinases, and Raf kinase then activates the MAP/ERK kinase 1 and 2 (MEK1/2) dual-specificity protein kinases, which in turn activate ERK1/2 (Robert P J and Der C J Oncogene 2007).
There is now considerable evidence that links dysregulation of the Ras/Raf/MEK/ERK pathway to oncogenesis in humans. Ras is hyperactivated in around 30% of human cancers, most commonly the K-Ras isoform. More specifically, Ras-activating mutations have been reported in about 90% of pancreatic carcinomas, 50% of colon carcinomas, 30% of lung cancers, and in around 30% of myeloid leukemia cases. Activating mutations of Raf have also been reported in around 7% of human cancers. In particular, mutations of B-RAF have been observed in over 60% of melanomas, around 30% of ovarian cancer cases, and in approximately 20% of colorectal carcinomas, as well as in several other malignancies at lower frequencies. Constitutively active MEK1/2 and ERK1/2 proteins are present in a relatively high number of human tumors, particularly those from the colon, lung, pancreas, ovary and kidney (Yap, J L et al. Chem Med Chem 2011).
A number of MAPK/ERK pathway inhibitors have been developed and are being evaluated in preclinical studies and in early clinical trials.
Therefore, the provision of new inhibitors of this pathway presents both a great therapeutic opportunity and a tremendous challenge for cancer therapy.